Biology subjects

Bradfield, L.

Publications and source records attributed to Bradfield, L..

5 recordsLinked to original sources

bioRxiv2026

Disrupting astrocyte signalling in the nucleus accumbens impairs incentive-driven instrumental actions

Astrocytes in the nucleus accumbens (NAC) core have been observed to undergo phenotypic changes associated with drug-seeking behaviour in both humans and animals. However, the role of NAC core astrocytes in non-drug-related instrumental behaviour remains poorly understood. To address this, we chemogenetically activated hM4Di receptors selectively expressed on NAC core astrocytes in rats during food-motivated decision-making tasks. In Experiment 1, rats were first trained to associate two auditory stimuli with two distinct food outcomes (pellets and sucrose), then to press left and right levers for those same outcomes. All training was conducted drug-free, and rats then received intraperitoneal (i.p) injections of either vehicle or deschloroclozapine (DCZ) prior to test. Disrupting astrocytic signalling via DCZ injections left instrumental choice intact when it was guided by cues signalling the sensory-specific properties of each outcome, as tested in specific Pavlovian instrumental transfer and outcome-selective reinstatement, but suppressed responding in an outcome devaluation test. In Experiment 2, a single stimulus and single lever were separately paired with distinct food outcomes, then presented together on test. Control animals demonstrated a general PIT effect, elevating responding during stimulus presentations, and this was prevented by Gi activation on NAC core astrocytes. Immunohistochemistry revealed increased neuronal activity following hM4Di activation in astrocytes. Together, these findings suggest that intact signalling in NAC core astrocytes is necessary for instrumental actions that depend on general arousal or affective processes, but not for actions guided by sensory-specific outcome expectations. Significance StatementAstrocyte dysfunction in the nucleus accumbens (NAC) has been implicated in several forms of compulsion in humans, yet preclinical work has focussed almost exclusively on drug-taking and seeking. The role of NAC core astrocytes on responding for non-drug outcomes is therefore unclear. Here, using food outcomes, we show that disrupting astrocytic Gi signalling in NAC core selectively impairs actions driven by general motivational states but spares those guided by specific outcome expectations. These findings suggest that NAC core astrocytes play a critical role in invigorating behaviour, extending their involvement beyond drug-seeking in animals and highlighting their potential relevance to compulsive behaviour more generally.

animal behavior and cognition↗

bioRxiv2024

Dorsomedial striatal neuroinflammation causes excessive goal-directed action control by disrupting homeostatic astrocyte function

Compulsive actions are typically thought to reflect the dominance of habits over goal-directed action. To address this, we mimicked the striatal neuroinflammation that is frequently exhibited in individuals with compulsive disorders in rats, by injecting the endotoxin lipopolysaccharide into the posterior dorsomedial striatum, and assessed the consequences for behavioural control. Surprisingly, this manipulation caused rats to acquire and maintain goal-directed actions under conditions that would otherwise produce habits. Immunohistochemical analyses indicated that these behaviours were a result of astrocytic proliferation. To probe this further, we chemogenetically activated the Gi-pathway in striatal astrocytes, which altered the firing properties of nearby medium spiny neurons and modulated goal-directed action control. Together, results show that striatal neuroinflammation is sufficient to bias action selection toward excessive goal-directed control via dysregulated astrocyte function. If translatable, our findings suggest that, contrary to conventional views, individuals with striatal neuroinflammation might be more prone to maladaptive goal-directed actions than habits, and future interventions should aim to restore appropriate action control.

animal behavior and cognition↗

bioRxiv2022

Cognitive effects of thalamostriatal degeneration are ameliorated by normalizing striatal cholinergic activity

The loss of neurons in parafascicular thalamus (Pf) and of their inputs to dorsomedial striatum (DMS) are associated with Lewy body disease (LBD) and Parkinsons disease dementia (PDD) and have been linked to the effects of neuroinflammation. In rats, these inputs regulate the function of striatal cholinergic interneurons (CINs) that are necessary for the flexible encoding of the action-outcome (AO) associations for goal-directed action. We found that these inputs modify the encoding, not retrieval, of new AO associations and cause burst-pause firing of CINs in the DMS during AO remapping. These adaptive effects were abolished by neuroinflammation in the Pf, resulting in the loss of goal-directed control when the rats were required to update AO associations after a change in contingency. We found that the neuronal and behavioral deficits induced by inflammation in the Pf were rescued by administration of selegiline, a MAO-B inhibitor that we found also enhances ATPase activity in CINs, suggesting a potential treatment for cognitive deficits associated with inflammation affecting the function of midline thalamic nuclei and related structures.

neuroscience↗

bioRxiv2021

Outcome-selective reinstatement is partially context-dependent, and associated with c-Fos activation in the posterior dorsomedial striatum

Research from human and animal studies has found that responding that has been successfully reduced following treatment can return upon exposure to certain contexts. An individual in recovery from alcohol use disorder, for example, might relapse to drinking upon visiting their favourite bar. However, most of these data have been derived from experiments involving a single (active) response, and the context-dependence of returned responding in situations involving choice between multiple actions and outcomes is less well-understood. We thus investigated how outcome-selective reinstatement - a procedure involving choice between multiple actions - was affected by altering the physical context in rats. In Experiment 1, rats were trained over 6 days to press a left lever for one food outcome (pellets or sucrose) and a right lever for the other outcome. Then, rats received an extinction session in either the same context (A) as lever press training, or in a different context (B). Rats were tested immediately (5 minutes) after extinction in Context A or B such that there were four groups in total: AAA, ABB, ABA, and AAB. Reinstatement testing consisted of one food outcome being delivered freely (i.e. unearned by lever pressing and unsignalled by cues) to the food magazine every 4 minutes in the following order: Sucrose, Pellet, Pellet, Sucrose. Selective reinstatement was considered intact if pellet delivery increased pressing selectively on the pellet lever, and sucrose delivery selectively increased pressing on the sucrose lever. This result (Reinstated > Nonreinstated) was observed for rats in group AAA and ABB, but not rats in groups ABA and AAB. Experiment 2 was conducted identically, except that rats received two extinction sessions over two days and tested one day later. This time, all groups demonstrated intact outcome-selective reinstatement regardless of context. Analysis of c-Fos expression in several brain regions revealed that only c-Fos expression in the posterior dorsomedial striatum (pDMS) was related to intact reinstatement performance. Overall, these results suggest that outcome-selective reinstatement is predominantly context-independent, and that intact reinstatement is related to neuronal activity in the pDMS. HighlightsO_LIOutcome-selective reinstatement is predominantly context-independent C_LIO_LIOutcome-selective reinstatement is entirely context-independent after multiple extinction sessions C_LIO_LIOutcome-selective reinstatement increases c-Fos expression in dorsomedial striatum C_LIO_LIc-Fos expression in orbitofrontal cortex and dorsal hippocampus is unaffected by selective reinstatement. C_LI

animal behavior and cognition↗

bioRxiv2019

Punishment insensitivity emerges from impaired contingency detection, not aversion insensitivity or reward dominance

Our behaviour is shaped by its consequences - we seek rewards and avoid harm. It has been reported that individuals vary markedly in their avoidance of detrimental consequences, i.e. in their sensitivity to punishment. The underpinnings of this variability are poorly understood; they may be driven by differences in aversion sensitivity, motivation for reward, and/or instrumental control. We examined these hypotheses by applying several analysis strategies to the behaviour of rats (n = 48; 18 female) trained in a task permitting concurrent assessment of punishment, reward-seeking, and Pavlovian fear. We show that punishment insensitivity is a unique phenotype, unrelated to differences in reward-seeking and Pavlovian fear, and due to a failure of instrumental control. Subjects insensitive to punishment are afraid of aversive events, they are simply unable to change their behaviour to avoid them.

neuroscience↗